Implantable calcium phosphate compositions and methods

ABSTRACT

An implantable composition is provided. The composition comprises porous ceramic granules. The porous ceramic granules comprise hydroxyapatite in an amount of about 8 to about 22 wt. % and beta-tricalcium phosphate in an amount of about 78 to about 92 wt. % based on a total weight of a ceramic granule. The composition includes a collagen carrier, and the porous ceramic granules have an average diameter from about 50 μm to 800 μm. Methods of making are also disclosed.

BACKGROUND

Bone defects or bone voids may be caused by a number of differentfactors, including but not limited to trauma, pathological disease orsurgical intervention. Because bone provides both stability andprotection to an organism, these defects or voids can be problematic. Inorder to address these defects or voids, compositions that contain bothnatural and synthetic materials have been developed. These compositionsmay, depending upon the materials contained within them, be used torepair tissues and to impart desirable biological and/or mechanicalproperties. In order to place these compositions, it is common to use amonolithic bone graft or to form an osteoimplant comprising particulatedbone in a carrier.

Another way to treat a bone defect or void is by employing bone puttiesor cements. Cements are typically used to assist in the attachment ofartificial implants to living bone, for bone repair and/or boneconstruction and putties are generally used to fill bone voids and tostimulate regeneration of bone in a patient. Cements and putties can bedesirable to use due to their handling characteristics such asflowability (e.g., cement) and moldability (e.g., putty) whichfacilitates placement into irregularly shaped bone repair sites (e.g.,bone defects or bone voids). For example, often, when the bone repairsite is a bone void, a surgeon may administer cement to the bone voidthrough the use of a cannula or may administer putty by molding andshaping the putty into the bone void by hand.

Typically, cements and putties are made from particulated bone dispersedin a biodegradable carrier material, such as alginate,carboxymethylcellulose (CMC), alkylene oxide copolymer (AOC), orpolyethylene glycol (PEG). While these carriers provide good handlingcharacteristics for administering to a bone repair site, they do notperform optimally for bone growth once implanted into a patient.

Further, cements and putties can include scaffolding materials, such as,biocompatible synthetic ceramics. However, while these materials can bebeneficial for bone growth, they can be difficult to incorporate insubstantial amounts into a composition that has a putty-like consistencysince these ceramics are generally larger in size, non-uniform, hard andbrittle. Moreover, the addition of large hard pieces of ceramic tends todisrupt the putty mass, producing a composition that can crumble and maylack the cohesiveness desired for handling prior to implantation and forpersistence after implantation.

Another problem with cements and putties is that they may be mutuallyexclusive and therefore, a putty may not be able to be altered into acement should one composition be more desirable than the other for useduring treatment of a bone repair site. Because of this, bothcompositions may be required to be on hand during the surgicalprocedure, which may not be ideal.

Therefore, there is a need to provide a composition that can be madeinto a moldable putty that can also be formed into a non-settableflowable cohesive cement or gel comprising porous ceramic granules and acollagen carrier. There is also a need to provide a composition that isideal for bone growth and has improved handling characteristics.

SUMMARY

Compositions are provided that are both moldable and flowable comprisingporous ceramic granules and a collagen carrier. The compositions areideal for bone growth and have improved handling characteristics.

In some embodiments, an implantable composition is provided. Thecomposition comprises porous ceramic granules. The porous ceramicgranules comprise hydroxyapatite in an amount of about 8 to about 22 wt.% and beta-tricalcium phosphate in an amount of about 78 to about 92 wt.% based on a total weight of a ceramic granule. The composition includesa collagen carrier, and the porous ceramic granules have an averagediameter from about 50 μm to 800 μm.

In some embodiments, a bone void filler is provided. The bone voidfiller comprises porous ceramic granules comprising hydroxyapatite in anamount of about 8 to about 22 wt. % and beta-tricalcium phosphate in anamount of about 78 to about 92 wt. %. The porous ceramic granules havean average diameter from about 50 μm to 800 μm. The bone void fillerincludes a collagen carrier comprising bovine type I collagen.

In some embodiments, a method of making a moldable and flowable bonevoid filler is provided. The method comprises adding porous ceramicgranules to a collagen carrier, the porous ceramic granules comprisinghydroxyapatite in an amount of about 8 to about 22 wt. % andbeta-tricalcium phosphate in an amount of about 78 to about 92 wt. %.

In some embodiments, a method of making porous ceramic granules isprovided. The method comprises heating pore-forming agent particles to atemperature above a glass transition temperature for the pore-formingagent particles; contacting the heated pore-forming agent particles witha ceramic material to form a mixture of pore-forming agent particles andceramic material; heating the mixture to remove the pore-forming agentparticles from the mixture to form a porous ceramic material; andmicronizing the porous ceramic material to obtain the porous ceramicgranules, wherein the porous ceramic granules have an average diameterfrom about 50 μm to 800 μm.

In some embodiments, porous ceramic granules are provided. The porousceramic granules are made by the process of heating pore-forming agentparticles to a temperature above a glass transition temperature for thepore-forming agent particles: contacting the heated pore-forming agentparticles with a ceramic material to form a mixture of pore-formingagent particles and ceramic material; heating the mixture to remove thepore-forming agent particles from the mixture to form porous ceramicmaterial; and micronizing the porous ceramic material to obtain theporous ceramic granules, wherein the porous ceramic granules have anaverage diameter from about 50 μm to 800 μm.

In some embodiments, a porous ceramic granule is provided. The porousceramic granule comprises hydroxyapatite in an amount of about 8 toabout 22 wt. % and beta-tricalcium phosphate in an amount of about 78 toabout 92 wt. %. The porous ceramic granule has a microporosity and adiameter of each of the micropores is less than about 10 μm, a BETsurface area from about 0.2 to about 10 m²/g, and an average diameterfrom about 50 μm to 800 μm.

While multiple embodiments are disclosed, still other embodiments of thepresent application will become apparent to those skilled in the artfrom the following detailed description, which is to be read inconnection with the accompanying drawings. As will be apparent, thepresent disclosure is capable of modifications in various obviousaspects, all without departing from the spirit and scope of the presentdisclosure. Accordingly, the detailed description is to be regarded asillustrative in nature and not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent regarding the following description,appended claims and accompanying drawings.

FIG. 1 is a flow chart of the method of making the porous ceramicgranules. The method comprises heating pore-forming agent particles to atemperature above a glass transition temperature for the pore-formingagent particles; contacting the heated pore-forming agent particles witha ceramic material to form a mixture of pore-forming agent particles andceramic material; heating the mixture to remove the pore-forming agentparticles from the mixture to form a porous ceramic material; andmicronizing the porous ceramic material to obtain the porous ceramicgranules, wherein the porous ceramic granules have an average diameterfrom about 50 μm to 800 μm.

FIG. 2 is a front view of pore-forming agent particles such aspolymethyl methacrylate (PMMA) that are fed through a plurality ofsieves to calibrate the pore-forming particles to a selected size foruse.

FIG. 3A is a SEM micrograph showing portions of the pore-forming agentparticles that overlap diameters when the particles coalesce andinterconnect.

FIG. 3B is an SEM micrograph of a portion of an interconnected porousstructure that is formed during heating of the pore-forming agentparticles in a thermoforming process.

FIG. 4 illustrates the steps in making a ceramic material slurry thatcontacts the heated pore-forming agent particles to form a mixture ofpore-forming agent particles and ceramic material. The ceramic materialcan be added to a mixing media to form a suspension or slurry.

FIG. 5 illustrates the steps in making the ceramic slurry of FIG. 4stirred before it contacts the heated pore-forming agent particles.

FIG. 6 illustrates a mixture of pore-forming agent particles and theceramic material.

FIG. 7 illustrates the various sized sieves used to make micronizedporous ceramic material that is formed after heating the mixture toremove the pore-forming agent particles from the mixture. The porousceramic material is illustrated being micronized by passing the porousceramic material through sieves of various sizes.

FIG. 8 is a perspective view of an automated crusher and an automatedsieve that in some embodiments, are used to micronize the porous ceramicmaterial.

FIG. 9 is a SEM micrograph of the porous ceramic granules. Themicrograph shows that the surface of the porous ceramic granules eachhave a concavity between 400 to about 600 microns.

FIG. 10 is a SEM micrograph of the porous ceramic granules. As shown,the granules contain microporosity.

FIG. 11 is a perspective view of an implantable composition. Theimplantable composition is in the form of a moldable putty. Thecomposition comprises porous ceramic granules. The porous ceramicgranules comprise hydroxyapatite in an amount of about 8 to about 22 wt.% and beta-tricalcium phosphate in an amount of about 78 to about 92 wt.% based on a total weight of a ceramic granule. The composition alsoincludes a collagen carrier. The porous ceramic granules have an averagediameter from about 50 μm to 800 μm.

FIG. 12 is a perspective view of the composition of FIG. 11 in anon-settable flowable cohesive cement or gel form disposed within asyringe.

FIG. 13 is a perspective view of the composition of FIG. 11 in puttyform being administered to a bone void or bone defect in the spine of apatient.

FIG. 14 is a perspective view of the putty of FIG. 13 disposed withinthe bone void or bone defect of the spine of a patient.

FIG. 15 is a perspective view of the non-settable flowable cohesivecement or gel form of FIG. 12 being administered to a bone void or bonedefect in a patient.

FIG. 16 is a perspective view of the non-settable flowable cohesivecement or gel form of FIG. 15 disposed within the bone void or bonedefect in a patient.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION Definitions

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Similarly, when values are expressed as approximations, by use of theantecedent “about,” it will be understood that the particular valueforms another embodiment that is +/−10% of the recited value.Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Also, as used inthe specification and including the appended claims, the singular forms“a,” “an,” and “the” include the plural, and reference to a particularnumerical value includes at least that particular value, unless thecontext clearly dictates otherwise. Ranges may be expressed herein asfrom “about” or “approximately” one particular value and/or to “about”or “approximately” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of this application are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Biocompatible, as used herein, is intended to describe materials that,upon administration in vivo, do not induce undesirable long-termeffects.

Bone, as used herein, refers to bone that is cortical, cancellous orcortico-cancellous of autogenous, allogenic, xenogenic, or transgenicorigin.

Bone graft, as used herein, refers to any implant prepared in accordancewith the embodiments described herein and therefore may includeexpressions such as a bone void filler.

The term “osteoinductive,” as used herein, refers to the quality ofbeing able to recruit cells from the host that have the potential tostimulate new bone formation. Any material that can induce the formationof ectopic bone in the soft tissue of an animal is consideredosteoinductive.

The term “osteoinduction” refers to the ability to stimulate theproliferation and differentiation of pluripotent mesenchymal stem cells(MSCs). In endochondral bone formation, stem cells differentiate intochondroblasts and chondrocytes, laying down a cartilaginous ECM, whichsubsequently calcifies and is remodeled into lamellar bone. Inintramembranous bone formation, the stem cells differentiate directlyinto osteoblasts, which form bone through direct mechanisms.Osteoinduction can be stimulated by osteogenic growth factors, althoughsome ECM proteins can also drive progenitor cells toward the osteogenicphenotype.

The term “osteogenic” refers to the ability of a graft material toproduce bone independently. To have direct osteogenic activity, thegraft must contain cellular components that directly induce boneformation. For example, an allograft seeded with activated MSCs wouldhave the potential to induce bone formation directly, withoutrecruitment and activation of host MSC populations. Because manyosteoconductive allografts also have the ability to bind and deliverbioactive molecules, their osteoinductive potential will be greatlyenhanced.

The term “patient” refers to a biological system to which a treatmentcan be administered. A biological system can include, for example, anindividual cell, a set of cells (e.g., a cell culture), an organ, or atissue. Additionally, the term “patient” can refer to animals,including, without limitation, humans.

The term “implantable” as utilized herein refers to a biocompatibledevice (e.g., the composition) retaining potential for successfulplacement within a mammal. The expression “implantable composition” andexpressions of the like import as utilized herein refers to an objectimplantable through surgery, injection, or other suitable means whoseprimary function is achieved either through its physical presence ormechanical properties. An example of the implantable device is thecomposition.

The term “thermoform” or “thermoforming” refers to the process where amaterial such as plastic is heated to a pliable forming or glasstransition temperature to form a specific shape in a mold.

The “debind,” or “debinding” refers to a process to remove a primarybinding material from a mold. The mold can be created through athermoforming process, as described above. Typically, there are multiplesteps to the debinding process, and the part goes through more than onecycle to ensure as much of the binding material is removed as possiblebefore sintering. After the debinding process, the part can besemi-porous, which can allow a secondary material to easily escapeduring a sintering cycle.

The term “amorphous” is defined a structure has no organization (not acrystalline structure), and the atomic structure resembles that of aliquid. Commonly, amorphous materials are amorphous solids unlessotherwise clarified. Amorphous materials are characterized by atomic ormolecular structures that are relatively complex and become ordered onlywith some difficulty. These materials are commonly prepared by rapidlycooling molten material. The cooling reduces the mobility of thematerial's molecules before they can pack into a more thermodynamicstate.

The term “crystalline” is defined as a material that consists primarilyof an organized crystal structure. A “crystal” is a solid composed ofatoms, ions, or molecules arranged in a pattern that is repetitive inthree-dimensions. Each crystal structure within a specific crystalsystem is defined by a unit cell. A unit cell is the smallest repeatablesubsection of the crystal.

The term “moldable” includes that the composition can be shaped by handor machine or injected into the target tissue site (e.g., bone defect,fracture, or void) into a wide variety of configurations to fit withinthe bone defect.

The term “flowable” includes that the composition can be administered inan injectable state via a syringe and/or cannula. The composition isflowable when its consistency is fluid-like and has a viscosity that islower than that of the viscosity of the composition when in a putty orpaste form. Flowable compositions include liquid (e.g., solution,suspension, or the like) or semi-solid compositions (e.g., gels,cements) that are easy to manipulate and may be brushed, sprayed,dripped, injected, shaped and/or molded at or near the target tissuesite. “Flowable” includes compositions with a low viscosity orwater-like consistency to those with a high viscosity, such as apaste-like material. In various embodiments, the flowability of thecomposition allows it to conform to irregularities, crevices, cracks,and/or voids in the bone defect site (e.g., bone void). For example, invarious embodiments, the composition may be used to fill one or morevoids in an osteolytic lesion.

The term “injectable” refers to a mode of administering the composition.The composition can be administered in a variety of ways such as, forexample, a syringe and/or cannula. For example, the composition can beadministered parenterally, such as for example, anterior lumbarinterbody administration for fusion, or posterior lumbar interbodyadministration for fusion or transforaminal lumbar interbodyadministration for fusion, other intraspinal injection or other localadministration.

Method of Making Porous Ceramic Granules

Methods of making a porous ceramic granule are provided that can betailored to have a specific size, porosity and microporosity thatprovide better handling characteristics when administered to a bonedefect in a bone void filler.

As shown in FIGS. 1-10, a method of making porous ceramic granules isprovided. The method allows the production of ceramic granules of aselected size, porosity, microporosity that have a specific surface areathat is beneficial for bone growth when administered to a bone defect asa bone graft such as, for example, a bone void filler.

As shown in the flow chart of FIG. 1, the method 20 comprises heating 22pore-forming agent particles 24 to a temperature above a glasstransition temperature for the pore-forming agent particles: contacting26 the heated pore-forming agent particles with a ceramic material 28 toform a mixture 30 of pore-forming agent particles and ceramic material;heating 32 the mixture to remove the pore-forming agent particles fromthe mixture to form a porous ceramic material 34; and micronizing 36 theporous ceramic material to obtain the porous ceramic granules 38,wherein the porous ceramic granules have an average diameter from about50 μm to 800 μm.

The pore-forming agent particles can be polymeric, such as, for example,a thermoplastic polymer. Thermoplastic polymers can include, but are notlimited to, polymethyl methacrylate (PMMA), polymethacrylate (PMA),polystyrene, polyethylene or a combination thereof. In some embodiments,the thermoplastic polymer selected is PMMA.

The pore-forming agent particles can be a specific size and eachparticle can have the same or different dimensions. It is contemplatedthat the particle size of the pore-forming agent particles can determinethe macropore size as well as the microporosity of the final porousceramic granules formed from the method. As shown in FIG. 2, a pluralityof stacked sieves 40 having different pore or mesh sizes can be used toseparate the pore-forming agent particles by size to obtain the selectedsize for use in the method.

For example, pore-forming agent particles that are selected for usewould be particles having a size range of from about 40 to about 700 μm.The particles, in some embodiments, can be in a range from about 500 toabout 670 μm, or from about 550 to about 600 μm. The pore-forming agentparticles can be from about 40, 50, 60, 70, 80, 90, 100, 105, 110, 115,120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185,190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255,260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325,330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395,400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465,470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535,540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605,610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675,680, 685, 690, 695 to about 700 μm.

The pore-forming agent particles can be an at least partially amorphousstructure or a completely amorphous structure so as to avoid too great avolume increase during heat treatment. In some embodiments, thepore-forming agent particles are in the form of beads. Other shapedparticles can be used including square, oval, irregularly shaped or acombination thereof.

The pore-forming agent particles are configured to degrade at a lowtemperature or a glass transition temperature such that the particlescan coalesce to form a monobloc or interconnected porous structure forthe ceramic material to interact with. For example, in the case of PMMA,the glass transition temperature is about 110° C. The pore-forming agentparticles can degrade at a low temperature with only a small amount ofresidual impurities and of non-corrosive decomposition products. Athermoforming process can be used to heat the pore-forming agentparticles.

As described above, the pore-forming agent particles are first heated toa temperature by a thermoforming process above a glass transitiontemperature for the selected pore-forming agent particles. For example,the temperature can be from 150 about to about 250° C. In someembodiments, the temperature can be from about 150° C. to about 180° C.The temperature can be from about 150, 155, 160, 165, 170, 175, 180,185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 to about250° C. The particles can be heated for a period of time from about 14to about 18 hours. The particles can be heated for a period time fromabout 14, 15, 16, 17 to about 18 hours.

When the pore-forming agent particles are heated above their glasstransition temperature, each of the particles contact one another andpartially interlock to fuse the particles together. Once the heatingstep is completed, a monobloc or interconnected porous structure 42 isin a fixed state and contains pores or spaces 44 between thepore-forming agent particles, as shown in FIG. 3B. The pore-formingagent particles will contain overlapping diameters which can bevisualized by a circle 46 on the exterior surface of each pore-formingagent particle, as shown in FIG. 3A. The circle indicates that aninterconnection between beads has occurred and the circle is aninterconnection rupture.

Prior to heating the pore-forming agent particles, the particles can beplaced into a container that can withstand thermal degradationtemperatures. The container can also be variously sized and shaped.Further, the container can be made from metal, plastic and/or aluminum.After the heating, the pore-forming agent particles now formed into themonobloc or interconnected porous structure can be placed into a newcontainer or mold. The mold can be a porous mold.

The next step is contacting the heated pore-forming agent particles witha ceramic material to form a mixture of pore-forming agent particles andceramic material. In this step, the mixture of ceramic material fills inthe pores or spaces created in between the pore-forming agent particles,as shown in FIG. 6. The mixture of ceramic material can be dispersed ina suspension or slurry 48. After contacting/adding the ceramic mixtureto the pore-forming agent particles, the mixture can be air dried for aperiod of time such as, for about 3 hours, and can be further dried in adryer for a period of time.

Before the ceramic material contacts with the heated pore-forming agentparticles, the suspension or slurry of ceramic material is prepared. Asshown in FIG. 4, the slurry or suspension can be made by adding theceramic material to an amount of mixing media that is disposed in acontainer forming a mixture. An amount of distilled water and dispersingagent is then added to the mixture, and the container is closed. Thecontainer is then placed on a mixing device. As shown in FIG. 5, thecontainer can then be placed on a balance to weigh the container withthe mixture and can be visually inspected to see if the mixture has a“milk like” appearance. The mixture is then filtered through a sieve toremove the mixing media from the mixture. The resulting slurry orsuspension is then placed into a second container. The weight of thecontainer and slurry or suspension can be taken, and finally thecontainer can be stirred with a stirring device (FIG. 5).

In some embodiments, the mixing media used to create the slurry orsuspension can include materials such as, for example, sodium acetatebuffer, sodium citrate buffer, sodium phosphate buffer, a Tris buffer(e.g., Tris-HCL), phosphate buffered saline (PBS), sodium phosphate,potassium phosphate, sodium chloride, potassium chloride, glycerol,calcium chloride or a combination thereof. In various embodiments, thebuffer concentration can be from about 1 mM to 100 mM. In someembodiments, the mixing media can further include sucrose, glycine,L-glutamic acid, sodium chloride, and/or polysorbate 80. Exemplaryorganic solvents or non-aqueous solvents include DMSO, acetic acid,acetone, DME, DMF, MTBE, acetonitrile, butanol, butanone, t-butylalcohol, ethanol, polyethylene glycol, methanol, chlorobenzene,chloroform, toluene, propanol, pentane, heptane, ethanol, diethyl ether,or the like.

In some embodiments, the mixing media can include a binding agent tohelp the slurry or suspension retain its shape when contacting theheated pore-forming agent particles. Examples of suitable binding agentsinclude, but are not limited to glycerol, polyglycerol, polyhydroxycompound, for example, such classes of compounds as the acyclicpolyhydric alcohols, non-reducing sugars, sugar alcohols, sugar acids,monosaccarides, disaccharides, water-soluble or water dispersibleoligosaccarides, polysaccarides and known derivatives of the foregoing.Specific polyhydroxy compounds include, 1,2-propanediol, glycerol,1,4-butylene glycol trimethylolethane, trimethylolpropane, erythritol,pentaerythritol, ethylene glycols, diethylene glycol, triethyleneglycol, tetraethylene glycol, propylene glycol, dipropylene glycol;polyoxyethylene-polyoxypropylene copolymer, for example, of the typeknown and commercially available under the trade names Pluronic andEmkalyx; polyoxyethylene-polyoxypropylene block copolymer, for example,of the type known and commercially available under the trade namePoloxamer; alkylphenolhydroxvpolyoxyethylene, for example, of the typeknown and commercially available under the trade name Triton,polyoxyalkylene glycols such as the polyethylene glycols, xylitol,sorbitol, mannitol, dulcitol, arabinose, xylose, ribose, adonitol,arabitol, inositol, fructose, galactose, glucose, mannose, sorbose,sucrose, maltose, lactose, maltitol, lactitol, stachyose, maltopentaose,cyclomaltohexaose, carrageenan, agar, dextran, alginic acid, guar gum,gum tragacanth, locust bean gum, gum arabic, xanthan gum, amylose,mixtures of any of the foregoing.

The ceramic material can comprise synthetic ceramic or ceramicsincluding hydroxyapatite and beta-tricalcium phosphate. The ceramicmaterial can be in a powder form. The ceramic material comprises acalcium to phosphate ratio of between 1.0 to about 2.0. In someembodiments, the calcium to phosphate ratio is between 1.0, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 to about 2.0.

The ceramic material is a biphasic calcium phosphate comprisinghydroxyapatite in an amount of about 8 to about 22 wt. % andbeta-tricalcium phosphate in an amount of about 78 to about 92 wt. %. Insome embodiments, the hydroxyapatite is in an amount of about 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 to about 22 wt. % and thebeta-tricalcium phosphate in an amount of about 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91 to about 92 wt. %.

The next step in the method is heating the mixture to remove thepore-forming agent particles from the mixture to form a porous ceramicmaterial. This step can be considered a debinding or demolding step. Inthis step, heat is applied to the mixture to burn out the pore-formingagent particles, creating voids in the place of the pore-forming agentparticles and leaving the porous ceramic material intact.

The mixture is heated at a temperature from about 200° C. to about 300°C. for a period of time and the heating can be done in an oven. Thetemperature can be from about 200, 205, 210, 215, 220, 225, 230, 235,240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295 to about 300°C. The heat treatment can be administered for a period of time fromabout 1 hour to about 20 hours. In some embodiments, the period of timeis from about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 to about 20 hours.

The next step in the method is micronizing the porous ceramic materialto obtain the porous ceramic granules. The ceramic material can begranules that can be micronized and/or passed through a sieve to obtainthe desired granule size. Micronization includes reducing the averagediameter of porous ceramic granules. Typically, micronization includesusing mechanical means to reduce the particle size of the porous ceramicgranules, such as for example, by granulation, crushing, bashing,milling and/or grinding.

In some embodiments, a mill can be used to micronize the ceramicmaterial, where the mill has a cylindrical drum that usually containsspheres. As the drum rotates the spheres inside collide with the ceramicmaterial, thus crushing them towards smaller diameters. In someembodiments, with grinding, the ceramic granules can be formed when thegrinding units of a device rub against each other while the granules aretrapped in between them.

In some embodiments, methods like crushing and/or cutting may also beused for reducing particle size of the ceramic material. Crushing canemploy, for example, hammer-like tools to break the porous ceramic intosmaller particles by means of impact. In some embodiments, cutting canuse sharp blades to cut the rough solid pieces into smaller ones. Thesemicronization techniques can reduce the particle size of the ceramic tothe micrometer size and these particles can be passed through one ormore sieves by hand or machine to obtain the desired particle size ofthe porous ceramic granules. The resulting porous ceramic granules willhave an average diameter from about 50 μm to 800 μm.

In some embodiments, the ceramic material is micronized by passing theceramic material through a sieve 50 using a crushing force, as shown inFIGS. 7 and 8. In some embodiments, the ceramic material is micronizedby a manual crusher 52, such as a pin brush and a manual sieve, shown inFIG. 7. In some embodiments, the ceramic material is micronized by anautomatic crusher 54 and an automatic sieve 56, shown in FIG. 8. Aplurality of sieves may be used for micronizing the ceramic material,which enables the granules to be sorted out based on size, as shown inFIG. 7. For example, a sieve with a larger mesh pore size can be usedfirst, followed by a subsequent sieve having a smaller mesh pore size.Each sieve used in a sequence can contain smaller mesh pore sizes thanthe previous sieve used. In some embodiments, the mesh pore sizes ofeach of the sieves can be from about 0.1 mm to about 4 mm. The mesh poresizes of each of the sieves can be from about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9 to about 4 mm.

As described above, after the micronizing step, the resulting porousceramic granules having an average diameter from about 50 μm to 800 μm.In some embodiments, the average diameter of the granules is from about90 μm to about 600 μm or from about 200 μm to about 500 μm. In someembodiments, the average diameter of the granules may be from about 50,55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130,135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200,205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270,275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340,345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410,415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480,485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550,555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620,625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690,695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760,765, 770, 775, 780, 785, 790, 795 to about 800 μm.

After the micronizing step, in some embodiments, the porous ceramicgranules can be optionally heated a second time to further debind thegranules. This additional heat treatment can heat the porous ceramicgranules at a temperature from about 200° C. to about 650° C. for a setperiod of time. The temperature can be from about 200, 205, 210, 215,220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285,290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355,360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425,430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495,500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565,570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635,640, 645 to about 650° C. The heat treatment can be administered over aperiod of time, such as, from about 1 hour to about 5 hours. In someembodiments, the heat treatment is administered from about 1, 2, 3, 4 toabout 5 hours.

A sintering step (58) can then be applied to the porous ceramic granulesto increase the cohesion and rigidity of the granules, as shown inFIG. 1. The resulting granules are microporous with controlledinterconnections and having an outer surface comprising a plurality ofconcave shapes, shown in FIG. 9 and as described herein.

The sintering step can occur in an oven at a temperature from about1000° C. to about 1400° C. for a period of time. In some embodiments,the temperature is from about 1000, 1010, 1020, 1030, 1040, 1050, 1060,1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180,1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300,1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390 to about 1400° C.The sintering step can be administered for a period of time from about 1to about 10 hours. In some embodiments, the period of time is from about1, 2, 3, 4, 5, 6, 7, 8, 9 to about 10 hours.

As described above, the porous ceramic granules each have amicroporosity and the diameter of each of the micropores is from about0.01 to about 10 microns, as shown in the SEM micrograph of FIG. 10. Insome embodiments, the diameter of each of the micropores is from about0.1 to about 10 microns or from about 1 to about 10 microns. In someembodiments, the diameter of each of the micropores can be from about0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 to about 10microns. In some embodiments, the porous ceramic granules have a percentmicroporosity from about 10 to about 100% or from about 10, 20, 30, 40,50, 60, 70, 80, 90 to about 100%.

The method described herein causes the porous ceramic granules to havean outer surface comprising a plurality of concave shapes 60, as shownin the SEM micrograph of FIG. 9. These concave surface features providethe granules with an irregular shape. The concave shapes can be disclike in appearance and can be a particular size. The concave shapes caneach have a diameter of from about 50 to about 1000 microns or fromabout 400 to about 600 microns. In some embodiments, each diameter canbe from about 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,350, 375, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455,460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525,530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595,600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925,950, 975 to about 1000 microns. In some embodiments, the micronizingstep is the step that causes the porous ceramic granules to have theconcave shapes on the outer surface.

When disposed in a bone graft, the concave surfaces on the outer surfaceof each granule can facilitate an increase in new bone attachment sincethe surface makes new bone attachment easier (e.g., vascularization andpenetration of associated cells) than attachment would be on a standardceramic granule. In some embodiments, the porous ceramic granulesfacilitate rapid and homogeneous osseointegration which supports bonehealing by acting as a scaffold over which bone can grow.

Each of the porous ceramic granules have a Brunauer-Emmett-Teller (BET)surface area from about 0.2 to about 10 m²/g. The BET surface area canbe from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6,7, 8, 9 to about 10 m²/g. The increase in surface area furtherfacilitates new bone growth by allowing the granules to dissolve andrelease calcium faster than a regular granule would.

In some embodiments, the porous ceramic granules are in an amorphousform, a crystalline form or a combination thereof. When the porousceramic granules are a combination of amorphous and crystalline, thegranules can be from about 2 to about 98% amorphous to from about 98 toabout 2% crystalline. When the granules are a combination of amorphousand crystalline, the granules can be from about 2, 4, 6, 8, 10, 12, 14,16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50,52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86,88, 90, 92, 94, 96 to about 98% amorphous and from about 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46,48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82,84, 86, 88, 90, 92, 94, 96 to about 98% crystalline.

The method can also include a sterilization step (62), as shown inFIG. 1. In some embodiments, the porous ceramic granules can besterilized by gamma radiation at a dose of about 15 kGy to about 40 kGyor about 25 kGy to about 40 kGy.

The porous ceramic granules can be packaged and stored for use. Invarious embodiments, the granules when packaged, can be sterilized byradiation in a terminal sterilization step. Terminal sterilization of aproduct provides greater assurance of sterility than from processes suchas an aseptic process, which require individual product components to besterilized separately and the final package assembled in a sterileenvironment.

In various embodiments, gamma radiation is used in the terminalsterilization step, which involves utilizing ionizing energy from gammarays that penetrates deeply into the granules. Gamma rays are highlyeffective in killing microorganisms, they leave no residues nor havesufficient energy to impart radioactivity to the composition. Gamma rayscan be employed when the granules are in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize the granules. E-beam radiation comprises a form of ionizingenergy, which is generally characterized by low penetration andhigh-dose rates. E-beam irradiation is similar to gamma processing inthat it alters various chemical and molecular bonds on contact,including the reproductive cells of microorganisms. Beams produced fore-beam sterilization are concentrated, highly-charged streams ofelectrons generated by the acceleration and conversion of electricity.

Other methods may also be used to sterilize the granules, including, butnot limited to, gas sterilization, such as, for example, with ethyleneoxide or steam sterilization.

In some embodiments, additional synthetic ceramics can be used to formthe porous ceramic granules. The synthetic ceramics disclosed herein maybe selected from one or more materials comprising calcium phosphateceramics or silicon ceramics. Biological glasses such ascalcium-silicate-based bioglass, silicon calcium phosphate, tricalciumphosphate (TCP), biphasic calcium phosphate, calcium sulfate,hydroxyapatite, coralline hydroxyapatite, silicon carbide, siliconnitride (Si₃N₄), and biocompatible ceramics may be used. In someembodiments, the ceramic is tri-calcium phosphate or biphasic calciumphosphate and silicon ceramics. In some embodiments, the ceramic istricalcium phosphate.

In some embodiments, the ceramics are a combination of a calciumphosphate ceramic and a silicon ceramic. In some embodiments, thecalcium phosphate ceramic is resorbable biphasic calcium phosphate (BCP)or resorbable tri-calcium phosphate (TCP).

In some embodiments, the biphasic calcium phosphate can have atricalcium phosphate:hydroxyapatite weight ratio of about 50:50 to about95:5, about 70:30 to about 95:5, about 80:20 to about 90:10, or about85:15.

The ceramics of the disclosure may also be oxide ceramics such asalumina (Al₂O₃) or zirconia (ZrO₂) or composite combinations of oxidesand non-oxides such as silicon nitride.

The porous ceramic granules can be used in a bone graft in any suitableapplication. For example, the granules can be administered in a bonegraft which can be utilized in a wide variety of orthopedic,periodontal, neurosurgical, oral and maxillofacial surgical proceduressuch as the repair of simple and/or compound fractures and/ornon-unions; external and/or internal fixations: joint reconstructionssuch as arthrodesis: general arthroplasty: cup arthroplasty of the hip:femoral and humeral head replacement; femoral head surface replacementand/or total joint replacement: repairs of the vertebral columnincluding spinal fusion and internal fixation: tumor surgery, e.g.,deficit filling: discectomy: laminectomy; excision of spinal cordtumors: anterior cervical and thoracic operations; repairs of spinalinjuries; scoliosis, lordosis and kyphosis treatments: intermaxillaryfixation of fractures: mentoplasty; temporomandibular joint replacement;alveolar ridge augmentation and reconstruction: inlay implantablematrices; implant placement and revision; sinus lifts; cosmeticprocedures; etc. Specific bones which can be repaired herein include theethmoid, frontal, nasal, occipital, parietal, temporal, mandible,maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbarvertebra, sacrum, rib, sternum, clavicle, scapula, humerus, radius,ulna, carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis,femur, tibia, fibula, patella, calcaneus, tarsal and/or metatarsalbones.

In accordance with some embodiments, the granules may be treated orchemically modified with one or more bioactive agents or bioactivecompounds. “Bioactive agent” or “bioactive compound,” as used herein,refers to a compound or entity that alters, inhibits, activates, orotherwise affects biological or chemical events. For example, bioactiveagents may include, but are not limited to, osteogenic or chondrogenicproteins or peptides; DBM powder: collagen, insoluble collagenderivatives, etc., and soluble solids and/or liquids dissolved therein:anti-AIDS substances; anti-cancer substances; antimicrobials and/orantibiotics such as erythromycin, bacitracin, neomycin, penicillin,polymycin B, tetracyclines, biomycin, chloromycetin, and streptomycins,cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamycin,etc.: immunosuppressants; anti-viral substances such as substanceseffective against hepatitis; enzyme inhibitors; hormones; neurotoxins:opioids; hypnotics; anti-histamines: lubricants; tranquilizers;anti-convulsants; muscle relaxants and anti-Parkinson substances:anti-spasmodics and muscle contractants including channel blockers:miotics and anti-cholinergics: anti-glaucoma compounds: anti-parasiteand/or anti-protozoal compounds; modulators of cell-extracellular matrixinteractions including cell growth inhibitors and antiadhesionmolecules; vasodilating agents: inhibitors of DNA, RNA, or proteinsynthesis; anti-hypertensives: analgesics: anti-pyretics: steroidal andnon-steroidal anti-inflammatory agents; anti-angiogenic factors:angiogenic factors and polymeric carriers containing such factors;anti-secretory factors: anticoagulants and/or antithrombotic agents;local anesthetics; ophthalmics; prostaglandins; anti-depressants;anti-psychotic substances; anti-emetics: imaging agents;biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids;peptides; vitamins; inorganic elements; co-factors for proteinsynthesis; endocrine tissue or tissue fragments: synthesizers; enzymessuch as alkaline phosphatase, collagenase, peptidases, oxidases, etc.;polymer cell scaffolds with parenchymal cells; collagen lattices;antigenic agents; cytoskeletal agents: cartilage fragments: living cellssuch as chondrocytes, bone marrow cells, mesenchymal stem cells; naturalextracts: genetically engineered living cells or otherwise modifiedliving cells: expanded or cultured cells; DNA delivered by plasmid,viral vectors, or other member; tissue transplants: autogenous tissuessuch as blood, serum, soft tissue, bone marrow, etc.: bioadhesives: bonemorphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin(FN); endothelial cell growth factor (ECGF); vascular endothelial growthfactor (VEGF); cementum attachment extracts (CAE); ketanserin: humangrowth hormone (HGH): animal growth hormones: epidermal growth factor(EGF); interleukins, e.g., interleukin-1 (IL-1), interleukin-2 (IL-2);human alpha thrombin; transforming growth factor (TGF-beta);insulin-like growth factors (IGF-1, IGF-2); parathyroid hormone (PTH);platelet derived growth factors (PDGF): fibroblast growth factors (FGF,BFGF, etc.); periodontal ligament chemotactic factor (PDLGF); enamelmatrix proteins; growth and differentiation factors (GDF); hedgehogfamily of proteins; protein receptor molecules: small peptides derivedfrom growth factors above; bone promoters; cytokines; somatotropin; bonedigesters; antitumor agents cellular attractants and attachment agents;immuno-suppressants; permeation enhancers. e.g., fatty acid esters suchas laureate, myristate and stearate monoesters of polyethylene glycol,enamine derivatives, alpha-keto aldehydes, etc.; and nucleic acids.

In one embodiment, the granules can include osteoinductive agentscomprising one or more members of the family of Bone MorphogeneticProteins (“BMPs”). BMPs are a class of proteins thought to haveosteoinductive or growth-promoting activities on endogenous bone tissue,or function as pro-collagen precursors. Known members of the BMP familyinclude, but are not limited to, BMP-1, BMP-2, BMP-3, BMP-4, BMP-5,BMP-6, BMP-7. BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14(GDF-5), BMP-15, BMP-16, BMP-17, BMP-18 as well as polynucleotides orpolypeptides thereof, as well as mature polypeptides or polynucleotidesencoding the same.

BMPs utilized as osteoinductive agents comprise one or more of BMP-1:BMP-2; BMP-3; BMP-4; BMP-5; BMP-6; BMP-7; BMP-8; BMP-9; BMP-10; BMP-11;BMP-12: BMP-13; BMP-15; BMP-16; BMP-17; or BMP-18; as well as anycombination of one or more of these BMPs, including full length BMPs orfragments thereof, or combinations thereof, either as polypeptides orpolynucleotides encoding the polypeptide fragments of all of the recitedBMPs. The isolated BMP osteoinductive agents may be administered aspolynucleotides, polypeptides, full length protein or combinationsthereof.

Indeed, the osteoinductive factors are the recombinant human bonemorphogenetic proteins (rhBMPs) because they are available in unlimitedsupply and do not transmit infectious diseases. In some embodiments, thebone morphogenetic protein is a rhBMP-2, rhBMP-4, rhBMP-7, orheterodimers thereof.

Recombinant BMP-2 can also be added to the granules. However, any bonemorphogenetic protein is contemplated, including bone morphogeneticproteins designated as BMP-1 through BMP-18. BMPs are available fromPfizer, a Delaware corporation and the BMPs and genes encoding them mayalso be prepared by one skilled in the art as described in U.S. Pat. No.5,187,076 to Wozney et al.; U.S. Pat. No. 5,366,875 to Wozney et al.;U.S. Pat. No. 4,877,864 to Wang et al.; U.S. Pat. No. 5,108,922 to Wanget al.; U.S. Pat. No. 5,116,738 to Wang et al.; U.S. Pat. No. 5,013,649to Wang et al.; U.S. Pat. No. 5,106,748 to Wozney et al.; and PCT PatentNos. WO93/00432 to Wozney et al.; WO94/26893 to Celeste et al.; andWO94/26892 to Celeste et al. All osteoinductive factors are contemplatedwhether obtained as above or isolated from bone. Methods for isolatingbone morphogenetic protein from bone are described, for example, in U.S.Pat. No. 4,294,753 to Urist and Urist et al., 81 PNAS 371, 1984.

In addition to the above, the granules may include one or more membersfrom the TGF-βsuperfamily. For example, the granules may include AMH,ARTN, GDF1, GDF10, GDF11, GDF15, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7,GDF8, GDF9, GDNF, INHA, INHBA, INHBB, INHBC, INHBE, LEFTY1, LEFTY2,MSTN, NODAL, NRTN, PSPN, TGFB1, TGFB2, TGFB3, FGF, basic FGF, VEGF,insulin-like growth factor, EGF, PDGF, nerve growth factor orcombinations thereof.

In certain embodiments, the bioactive agent may be a drug. In someembodiments, the bioactive agent may be a small molecule, a growthfactor, cytokine, extracellular matrix molecule, or a fragment orderivative thereof, for example, a protein or peptide sequence such asRGD.

Implantable Compositions

As shown in FIGS. 11-16, an implantable composition 64 is provided. Theimplantable composition can be a bone graft such as a bone void fillerand is configured to be both moldable and flowable. The composition isalso ideal for bone growth and has improved handling characteristics.The composition comprises the porous ceramic granules 38, as describedabove with regard to the method and a collagen carrier 66, as shown inFIGS. 9 and 11, 12. The porous ceramic granules may be of a selectedsize, porosity, microporosity and have a specific surface area that isbeneficial for bone growth when administered to a surgical site.

The porous ceramic granules comprise hydroxyapatite and beta-tricalciumphosphate. The hydroxyapatite is in an amount of about 8 to about 22 wt.% based on a total weight of a ceramic granule. The hydroxyapatite canbe in a range from about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21 to about 22 wt. %. In some embodiments, the hydroxyapatite can bein a range from about 1 to about 99 wt. %, such as from 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98 to about 99 wt. %.

The beta-tricalcium phosphate is in an amount of about 78 to about 92wt. % based on a total weight of a ceramic granule. The beta-tricalciumphosphate can be in an amount from about 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91 to about 92 wt %. In some embodiments, thebeta-tricalcium phosphate can be in a range from about 1 to about 99 wt.%, such as from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98 to about 99 wt. %.

The porous ceramic granules can have a calcium to phosphate ratio ofbetween 1.0 to about 2.0. In some embodiments, the calcium to phosphateratio is between 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 toabout 2.0.

The porous ceramic granules have an average diameter from about 50 μm to800 μm. In some embodiments, the average diameter of the granules isfrom about 90 μm to about 600 μm or from about 200 μm to about 500 μm.In some embodiments, the average diameter of the granules may be fromabout 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120,125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190,195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260,265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330,335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400,405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470,475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540,545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610,615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680,685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750,755, 760, 765, 770, 775, 780, 785, 790, 795 to about 800 μm.

The porous ceramic granules have an interconnected porous structurehaving microporosity, as shown in the SEM micrograph of FIG. 10. Thediameter of each of the micropores is from about 0.01 to about 10microns. In some embodiments, the diameter of each of the micropores canbe from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 toabout 10 microns.

As described above, each of the porous ceramic granules have an outersurface comprising the plurality of concave shapes 60, as shown in theSEM micrograph of FIG. 9. These concave surface features provide thegranules with an irregular shape. The concave shapes can be disc like inappearance and can be a particular size. The concave shapes can eachhave a diameter from about 50 to about 1000 microns or from about 400 toabout 600 microns. In some embodiments, each diameter can be from about50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400,405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470,475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540,545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 625, 650,675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975 to about1000 microns.

The concave surfaces on the outer surface of each granule can facilitatean increase in new bone attachment since the surface makes new boneattachment easier (e.g., vascularization and penetration of associatedcells) than attachment would be on a standard ceramic granule. In someembodiments, the porous ceramic granules facilitate rapid andhomogeneous osseointegration which supports bone healing by acting as ascaffold over which bone can grow.

Each of the porous ceramic granules have a Brunauer-Emmett-Teller (BET)surface area from about 0.2 to about 10 m²/g. The BET surface area canbe from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6,7, 8, 9 to about 10 m²/g. The increase in surface area furtherfacilitates new bone growth by allowing the granules to dissolve andrelease calcium faster than a regular granule would.

The porous ceramic granules can be in an amorphous form, a crystallineform or a combination thereof. When the porous ceramic granules are acombination of amorphous and crystalline, the granules can be from about2 to about 98% amorphous to from about 98 to about 2% crystalline. Whenthe granules are a combination of amorphous and crystalline, thegranules can be from about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60,62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96to about 98% amorphous and from about 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54,56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90,92, 94, 96 to about 98% crystalline.

The porous ceramic granules can be disposed in or on the collagencarrier. The composition can include from about 50 to about 98 wt. %porous ceramic granules and from about 2 to about 50 wt. % collagencarrier based on a total weight of the composition. The composition caninclude from about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 toabout 98 wt. % porous ceramic granules and from about 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49 to about 50 wt. % collagen carrier based on thetotal weight of the composition.

The collagen carrier can be porcine or bovine collagen. In someembodiments, the collagen carrier comprises bovine type I collagen. Thecollagen carrier can be made from soluble collagen and/or insolublecollagen; and the collagen carrier can be cross-linked collagen,partially cross-linked collagen, or is not cross-linked collagen.

The composition can be in a putty, paste, or non-settable flowablecohesive cement or gel form. The putty, paste, non-settable flowablecohesive cement or gel can be moldable and/or injectable. Thecomposition can also be formed into a moldable putty or paste and thencan be converted into a non-settable flowable cohesive cement or gel. Insome embodiments, the composition can be formed into a non-settableflowable cohesive cement or gel initially and can then be converted intoa putty or paste. For example, as shown in FIGS. 11 and 13-14, thecomposition can be administered in a putty form 68 to a surgical sitesuch as a bone void 70 in a patient P. As shown in FIGS. 12, 15 and 16,the composition can also be administered in a non-settable flowablecohesive cement or gel form 72 to the bone void. When the composition isin the non-settable flowable cohesive cement or gel form, it is flowableand can be delivered through a syringe 74.

In some embodiments, the flowable composition has a flowable viscositystarting from about 50 Pascal-second (Pa-s), 100 Pa-s, 150 Pa-s, 200Pa-s, 250 Pa-s, to about 300 Pa-s and reaches a higher viscosity fromabout 500 Pa-s, 750 Pa-s, 1000 Pa-s, 1500, 2000 Pa-s, 2500 Pa-s to about3000 Pa-s. In some embodiments, the flowable composition has a flowableviscosity starting from about 50 Pa-s to about 3000 Pa-s and reaches ahigher viscosity from about 3000 Pa-s to about 300,000 Pa-s.

The syringe, in some embodiments, used to deliver the flowablecomposition (e.g., the non-settable flowable cohesive cement or gel) caninclude a 7-8 mm bore or a 6-14 mm bore.

The composition can be lyophilized and non-hydrated for storage. A fluidsuch as, bone marrow aspirate, saline, sterile water for injection,phosphate buffered saline, dextrose, Ringer's lactated solution, or acombination thereof can be used to hydrate the composition prior to use.In some embodiments, when the composition is lyophilized andnon-hydrated, the fluid can rehydrate the composition into the puttyform. The composition can be rehydrated with a fluid to form a putty ata ratio from about 0.5 to about 1.5 vol./vol. In some embodiments, thecomposition can be rehydrated at a 1:1 vol./vol or a 1:1.5 vol./vol.ratio of composition to water to form the moldable paste or putty. Thecomposition in its putty form can then be further hydrated to form asuper hydrated non-settable flowable cohesive cement or gel. The puttycan be further hydrated at a 150%: 200% vol./vol. ratio. Alternatively,in some embodiments, the lyophilized and non-hydrated composition can behydrated with the fluid to form the non-settable flowable cohesivecement or gel. The composition is capable of forming into a putty and anon-settable flowable cohesive cement or gel due to the outer surface ofthe porous ceramic granules comprising the plurality of concave shapes,as described above and shown in the SEM micrograph of FIG. 9. Theplurality of concave shapes reduces hydration time and increasehydration uniformity.

In some embodiments, prior to hydration, the composition can besterilized by gamma radiation administered at a dose from about 15 toabout 40 kGy for a period of time. The gamma radiation can be from about15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39 to about 40 kGy.

The composition can have a certain density before and after hydration.For example, the composition when lyophilized and non-hydrated can havea density from about 0.2 to about 0.8 g/cc or from about 0.25 to about0.6 g/cc. In some embodiments, the lyophilized and non-hydratedcomposition can have a density from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7to about 0.8 g/cc. When the composition is hydrated, the density can befrom about 1.2 to about 2.0 g/cc or from about 1.4 o about 1.6 g/cc. Insome embodiments, the hydrated composition can have a density from about1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 to about 2.0 g/cc.

The composition can have a modulus of elasticity from about 2 MPa toabout 12 MPa, such as from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 to about12 MPa. The modulus of elasticity can change depending on the form thatthe composition is in (e.g., hydration level). For example, the modulusof elasticity of the composition will be higher as the hydration levelis decreased and is in the putty form, and the modulus of elasticity ofthe composition will be lower as the hydration level is increased and isin a non-settable flowable cohesive cement or gel form. In someembodiments, the modulus of elasticity will decrease as the ceramiccontent is decreased.

As described above, the composition can be lyophilized and when in puttyform, can be lyophilized into shapes. Shapes include, but are notlimited to indented rectangles, indented discs, indented squares,indented triangles or indented cylinders. The indentation may be used tofacilitate re-hydration with the fluid. The indentation can be similarto the indents found in U.S. Pat. No. 7,824,703, assigned to WarsawOrthopedic Inc, which is incorporated by reference in its entirety. Insome embodiments, re-hydration can be from about 1 second to about 1minute or from about 1 minute to about 60 minutes. In some embodiments,re-hydration can be from about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,55 seconds, 1 minute, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59 to about 60 minutes.

After the composition is hydrated into putty, autograft bone can beadded to the putty and the modulus of elasticity can be increased withthe addition of the autograft bone. The putty will maintain itsmoldability and cohesiveness even with the addition of autograft bone.In some embodiments, autograft bone can also be added to the compositionwhen it is the non-settable flowable cohesive cement or gel form.

The autograft bone can be cut into various shapes, including fibers,chips, granules, powder, shards, shavings or a combination thereof. Theautograft bone can be cut into specific sizes. For example, theautograft bone can be from about 1 to about 20 mm. In some embodiments,the size of the autograft bone added to the composition can be fromabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19to about 20 mm.

A certain amount of autograft bone can be added to the composition, suchas from about 0 to about 50 vol. % or from about 0.1, 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 toabout 50 vol. % based on the total weight of the composition. In someembodiments, the composition can contain greater than 50 vol. % ofautograft bone without the composition losing its cohesive properties.

In some embodiments, the autograft can be autograft bone chips having asize from about 1 to about 20 mm or from about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 to about 20 mm.

In some embodiments, the fluid used to hydrate the composition caninclude sterile water, saline, phosphate buffered saline (PBS),hyaluronic acid, cellulose ethers (such as carboxymethyl cellulose),water, collagen, gelatin, autoclaved bone powder, osteoconductivecarriers, whole blood, blood fractions, concentrated bone marrowaspirate, and mixtures thereof. Non-limiting examples of blood fractionsinclude serum, plasma, platelet-rich plasma, concentrated platelet-richplasma, platelet-poor plasma, and concentrated platelet poor plasma.

A viscosity enhancing agent can be added to the composition including,but not limited to mannitol, trehalose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxyethyl methylcellulose,carboxymethylcellulose and salts thereof, Carbopol,poly-(hydroxyethyl-methacrylate), poly-(methoxyethylmethacrylate),poly(methoxyethoxyethylmethacrylate), polymethyl-methacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,mPEG, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG900, PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinationsthereof.

In some embodiments, additional materials may be added to thecomposition such as one or more of poly (alpha-hydroxy acids),polyglycolide (PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids), polyorthoesters (POE), polyaspirins,polyphosphagenes, gelatin, hydrolyzed gelatin, fractions of hydrolyzedgelatin, elastin, starch, pre-gelatinized starch, hyaluronic acid,chitosan, alginate, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D,L-lactide, orL-lactide, caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol(PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates,PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, POE, SAIB (sucrose acetateisobutyrate), polydioxanone, methylmethacrylate (MMA), MMA andN-vinylpyyrolidone, polyamide, oxycellulose, copolymer of glycolic acidand trimethylene carbonate, polyesteramides, polyether ether ketone,polymethylmethacrylate, silicone, hyaluronic acid, or combinationsthereof.

In some embodiments, the composition alternatively or in additioncomprises at least one biodegradable polymer carrier comprising one ormore of poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone, L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone),poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide),poly(L-lactide), poly(esteramide), carboxymethylcellulose (CMC),alkylene oxide copolymer (AOC) or a combination thereof.

A method of making a moldable and flowable bone void filler is alsoprovided. It is to be understood that the moldable and flowable bonevoid filler is the composition, as described herein. The methodcomprises adding porous ceramic granules to a collagen carrier, theporous ceramic granules comprising hydroxyapatite in an amount of about8 to about 22 wt. % and beta-tricalcium phosphate in an amount of about78 to about 92 wt. %. In some embodiments, the composition comprisesfrom about 50 to about 98 wt. % porous ceramic granules and from about 2to about 50 wt. % collagen carrier.

Lyophilization

As described herein, the composition can be lyophilized. Thelyophilization process typically includes sublimation of water from afrozen formulation under controlled conditions. Lyophilization can becarried out using standard equipment as used for lyophilization orvacuum drying. The cycle may be varied depending upon the equipment andfacilities used for the fill and finish.

Initially, in some embodiments, the composition is placed in alyophilization chamber under a range of temperatures and then subjectedto temperatures well below the freezing point of DBM, generally forseveral hours. After freezing is complete, the lyophilization chamberand the condenser are evacuated through vacuum pumps, the condensersurface having been previously chilled by circulating refrigerant. Thecondenser will have been chilled below the freezing point of thecomposition. Additionally, evacuation of the chamber should continueuntil a pressure of about 50 mTorr to about 600 mTorr, preferably about50 to about 150 mTorr is obtained.

The lyophilized composition is then warmed under vacuum in the chamberand condenser. This usually will be carried out by warming the shelveswithin the lyophilizer on which the lyophilized composition rests duringthe lyophilization process at a pressure ranging from about 50 mTorr toabout 600 mTorr. The warming process will optimally take place verygradually, over the course of several hours. Complete drying can beaccomplished by stabilization of vacuum, condenser temperature andlyophilized composition shelf temperature. After the initial drying, thetemperature of the lyophilized composition can be increased andmaintained for several hours. Once the drying cycle is completed, thepressure in the chamber can be slowly released to atmospheric pressure(or slightly below) with sterile, dry-nitrogen gas (or equivalent gas).

In some embodiments, after lyophilization, the composition is from about95 to about 99.5% free of moisture. The composition can be from about95, 95.5, 96, 96.5, 97, 97.5, 98, 98.5, 99, to about 99.5% free ofmoisture. In some embodiments, the composition has about 0.5% to about5% moisture content remaining after lyophilization. In variousembodiments, the composition has from about 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5 to about 5% moisture content remaining after lyophilization. Thelyophilized composition is stable and can be stored at a wide range oftemperatures.

These and other aspects of the present application will be furtherappreciated upon consideration of the following Example, which isintended to illustrate a certain particular embodiment of theapplication but is not intended to limit its scope, as defined by theclaims.

Kits

In some embodiments, the composition and/or the porous ceramic granulesalone may be packaged in a moisture resistant sterile package. In use,the porous ceramic granules can be added to a bone graft or thecomposition with the porous ceramic granules within or on thecomposition can be administered to an orthopedic site.

In various embodiments, a kit is provided comprising the compositionand/or the porous ceramic granules separate from the composition. Thekit may include additional parts along with the composition or granulescombined together to be used to administer the bone graft (e.g., wipes,needles, syringes, mixing syringe or other mixing device, etc.). The kitmay include the porous ceramic granules or the porous ceramic granulesalready added to composition in a first compartment. The secondcompartment may include the composition if the granules have not beenadded to the bone graft and any other instruments needed for thedelivery. A third compartment may include a fluid for hydrating thecomposition. A fourth compartment may include gloves, drapes, wounddressings and other procedural supplies for maintaining sterility of theimplanting process, as well as an instruction booklet, which may includea chart that shows how to administer the composition. A fifthcompartment may include additional needles and/or sutures. Each tool maybe separately packaged in a plastic pouch that is sterilized. A sixthcompartment may include an agent for radiographic imaging. A cover ofthe kit may include illustrations of the implanting procedure and aclear plastic cover may be placed over the compartments to maintainsterility. In some embodiments, the composition within the kit ispre-formed into a moldable putty or paste or a non-settable flowablecohesive cement or gel.

These and other aspects of the present application will be furtherappreciated upon consideration of the following Example, which isintended to illustrate a certain particular embodiment of theapplication but is not intended to limit its scope, as defined by theclaims.

EXAMPLES Example 1

Porous Ceramic Granules

Porous ceramic granules are contemplated that are made from the methoddescribed in the flowchart of FIG. 1 and described above. The porousceramic granules have an average diameter from about 50 μm to 800 μm,comprise a biphasic calcium phosphate comprising hydroxyapatite in anamount of about 8 to about 22 wt. % and beta-tricalcium phosphate in anamount of about 78 to about 92 wt. %, have a microporosity and thediameter of each of the micropores is from about 0.1 to about 10microns, comprise an outer surface comprising a plurality of concaveshapes each having a diameter of from about 400 to about 600 microns andeach of the porous ceramic granules have a BET surface area from about0.2 to about 10 m²/g.

Example 2

Implantable Composition

An implantable composition is contemplated that can be in the form of amoldable putty or a non-settable flowable cohesive cement or gel. Theimplantable composition can be dehydrated and then hydrated into amoldable putty. The moldable putty can then be further hydrated into anon-settable flowable cohesive cement or gel.

It is contemplated that the implantable composition comprises porousceramic granules comprising hydroxyapatite in an amount of about 8 toabout 22 wt. % and beta-tricalcium phosphate in an amount of about 78 toabout 92 wt. % based on a total weight of a ceramic granule; and acollagen carrier. The porous ceramic granules have an average diameterfrom about 50 μm to 800 μm. The composition comprises from about 50 toabout 98 wt. % porous ceramic granules and from about 2 to about 50 wt.% collagen carrier based on a total weight of the composition. Thecollagen carrier is porcine or bovine collagen and the implantablecomposition has a modulus of elasticity from about 2 MPa to about 12MPa. The implantable composition can be hydrated with bone marrowaspirate.

Example 3

Implantable Composition

An implantable composition is contemplated that can be in the form of amoldable putty or a non-settable flowable cohesive cement or gel. Theimplantable composition can be dehydrated and then hydrated into amoldable putty and/or a non-settable flowable cohesive cement or gel.

The implantable composition comprises porous ceramic granules comprisinghydroxyapatite in an amount of about 15 wt. % and beta-tricalciumphosphate in an amount of about 85 wt. % based on a total weight of aceramic granule and a collagen carrier. The calcium to phosphate ratiois 1.525. The porous ceramic granules have an average diameter fromabout 200 μm to 500 μm. The composition comprises from about 77 to about93 wt. % porous ceramic granules and from about 7 to about 23 wt. %collagen carrier based on a total weight of the composition. Thecollagen carrier is bovine type I collagen and the plurality of concaveshapes on the outer surface of the granules each have a diameter fromabout 400 to about 600 microns. The porous ceramic granules containmicroporosity and the volume of the microporosity is from about 0.01 toabout 10 microns. Each of the porous ceramic granules have a BET surfacearea from about 0.2 to about 0.6 m²/g. The implantable composition canbe hydrated with bone marrow aspirate.

Although the invention has been described with reference to preferredembodiments, persons skilled in the art will recognize that changes maybe made in form and detail without departing from the spirit and scopeof the invention.

What is claimed is:
 1. An implantable composition comprising porousceramic granules, the porous ceramic granules comprising hydroxyapatitein an amount of about 8 to about 22 wt. % and beta-tricalcium phosphatein an amount of about 78 to about 92 wt. % based on a total weight of aceramic granule; and a collagen carrier, the porous ceramic granuleshaving an average diameter from about 50 μm to 800 μm, wherein theporous ceramic granules comprise an interconnected porous structure andan outer surface comprising a plurality of concave shapes each having adiameter of about 400 to about 600 microns.
 2. The implantablecomposition of claim 1, wherein (i) the porous ceramic granules aredisposed in or on the collagen carrier; (ii) the implantable compositionis a putty, paste, or cement; (iii) the implantable composition is aflowable putty, flowable paste, or a flowable cement; or (iv) theimplantable composition is injectable.
 3. The implantable composition ofclaim 1, wherein the composition comprises from about 50 to about 98 wt.% porous ceramic granules and from about 2 to about 50 wt. % collagencarrier based on a total weight of the composition.
 4. The implantablecomposition of claim 1, wherein (i) the porous ceramic granules have acalcium to phosphate ratio of between 1.0 to about 2.0; or (ii) theporous ceramic granules are in crystalline or amorphous forms.
 5. Theimplantable composition of claim 1, wherein the porous ceramic granulesare in a combination of crystalline and amorphous forms.
 6. Theimplantable composition of claim 1, wherein the porous ceramic granuleshave an average diameter (i) from about 90 μm to about 600 μm; or (ii)from about 200 μm to about 500 μm.
 7. The implantable composition ofclaim 1, wherein (i) the porous ceramic granules each have amicroporosity, and the volume of the microporosity is from about 0.01 toabout 10 microns.
 8. The implantable composition of claim 1, whereineach of the porous ceramic granules have a Brunauer-Emmett-Teller (BET)surface area from about 0.2 to about 10 m²/g.
 9. The implantablecomposition of claim 1, wherein (i) the collagen carrier is porcine orbovine collagen; (ii) the collagen carrier comprises bovine type Icollagen; (iii) the collagen carrier is soluble collagen and/orinsoluble collagen; or (iv) the collagen carrier is cross-linkedcollagen, partially cross-linked collagen, or is not cross-linkedcollagen.
 10. The implantable composition of claim 1, wherein theimplantable composition has a modulus of elasticity from about 2 MPa toabout 12 MPa.
 11. The implantable composition of claim 1, wherein theimplantable composition is hydrate with bone marrow aspirate, saline,sterile water for injection, phosphate buffered saline, dextrose,Ringer's lactated solution, or a combination thereof.
 12. Theimplantable composition of claim 1, wherein the implantable compositionis delivered through a syringe having a 7-8 mm bore.
 13. A bone voidfiller comprising porous ceramic granules comprising hydroxyapatite inan amount of about 8 to about 22 wt. % and beta-tricalcium phosphate inan amount of about 78 to about 92 wt. %, the porous ceramic granuleshaving and an average diameter from about 50 μm to 800 μm; and acollagen carrier comprising bovine type I collagen, wherein the porousceramic granules comprise an interconnected porous structure and anouter surface comprising a plurality of concave shapes each having adiameter of about 400 to about 600 microns.
 14. The bone void filler ofclaim 13, wherein (i) the porous ceramic granules each have amicroporosity, and the volume of the microporosity is from about 0.01 toabout 10 microns; or (ii) the porous ceramic granules have a BET surfacearea from about 0.2 to about 10 m²/g.
 15. The bone void filler of claim13, wherein (i) the porous ceramic granules are disposed in or on thecollagen carrier; (ii) the bone void filler is a putty, paste, orcement; (iii) the bone void filler is a flowable putty, flowable paste,or a flowable cement; or (iv) the bone void filler is injectable. 16.The bone void filler of claim 13, wherein the bone void filler comprisesfrom about 50 to about 98 wt. % porous ceramic granules and from about 2to about 50 wt. % collagen carrier.
 17. The bone void filler of claim13, wherein the porous ceramic granules have a calcium to phosphateratio between 1.0 to about 2.0.
 18. A method of making a moldable andflowable bone void filler, the method comprising adding porous ceramicgranules to a collagen carrier, the porous ceramic granules comprisinghydroxyapatite in an amount of about 8 to about 22 wt. % andbeta-tricalcium phosphate in an amount of about 78 to about 92 wt. %.19. The method of claim 18, wherein the composition comprises from about50 to about 98 wt. % porous ceramic granules and from about 2 to about50 wt. % collagen carrier.